Proton therapy for pituitary adenoma

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Pituitary adenomas arise from the adenohypophysis and represent
approximately 10% to 15% of all primary brain tumors. Tumor
classification is divided by size and functional characteristics.1
Morbidities owing to tumor size include visual and neurological defects
due to proximity to the optic chiasm and cavernous sinuses. Perhaps the
most important distinction in classifying pituitary adenomas is
functional capacity. Secretory adenomas may cause potentially fatal
biochemical imbalances because of overproduction of pituitary hormones
like prolactin, growth hormones, adrenocorticotropic hormones and, more
infrequently, thyroid-stimulating hormones.2 Standard
treatment for nonfunctioning macroadenomas is transsphenoidal resection,
and functioning adenomas can be medically managed when indicated.

Radiation therapy (RT) is used in the adjuvant setting after a
subtotal resection or as a primary treatment for symptomatic primary or
recurrent gross disease that is not amenable to surgical excision and
cannot be medically managed. External-beam RT (EBRT) results in
excellent radiographic disease control rates, ranging from 80% to 98% in
nonfunctioning adenomas and 67% to 89% in functioning adenomas.3
While photon-based RT has consistently produced high tumor control with
low toxicity, room remains for improving the therapeutic ratio,
especially in younger patients who may be at greatest risk from
radiation-induced late effects. Hypopituitarism of 1 or more axes is by
far the most common adverse effect, with a 20% 5-year incidence rising
to nearly 80% within 15 years of follow-up. Less frequent toxicities
include visual and neurological complications, secondary tumors,
cerebral vascular accidents, and cerebral necrosis.4,5

The advantage of proton therapy over conventional RT is a potential
for decreased late effects of radiation attributable to lower doses to
adjacent normal tissues. While there is little hope that pituitary
function will be spared, additional toxicities may be avoided given the
more favorable dose distribution. Dosimetric studies comparing different
radiotherapy modalities suggest proton therapy could improve the
therapeutic ratio in pituitary adenoma treatment by reducing the dose to
the retinas, optic nerves, brainstem, and temporal lobes compared with
conventional photon techniques including intensity-modulated radiation
therapy (IMRT).6,7 In addition, proton therapy reduces the
dose to the hippocampi, thus lowering radiation exposure to the neural
stem cells, which may lessen the neurocognitive impact of radiotherapy.8
To date, the literature regarding proton therapy for pituitary adenoma
is sparse. We have conducted a retrospective review of patients treated
at our institution with proton therapy for pituitary adenoma in an
effort to contribute to the literature.

Patients and methods

In accordance with an institutional review board-approved protocol
and the Health Insurance Portability and Accountability Act (HIPAA), we
reviewed the medical records of 17 patients with pituitary adenomas
treated between 2007 and 2013 at the University of Florida Proton
Therapy Institute in Jacksonville. All patients were treated with
curative intent using three-dimensional conformal proton therapy. All
patients were radiographically evaluated with computed tomography (CT)
and/or magnetic resonance imaging (MRI) before and after treatment. In
addition, all patients’ pituitary adenoma diagnoses were histologically
confirmed prior to RT. Only benign pituitary tumors were included in the
study; pituitary carcinomas were excluded from analysis. Patients
treated with modalities other than transsphenoidal or transcranial
surgical resection, such as stereotactic radiosurgery (SRS), were also
excluded from our study.

Follow-up was calculated from the date the patient initiated RT.
Length of follow-up ranged from 0.3 to 5.7 years, with a median time of
3.0 years. Patient, tumor, and treatment characteristics are presented
in Table 1. All but 1 patient underwent surgery before proton therapy.
Of the 16 who received surgery, 15 underwent transsphenoidal resection,
and 1 was resected via transcranial approach followed by a second
transsphenoidal operation. In total, 5 patients received a second
operation before proton therapy. All patients had measurable gross
disease at the time of proton therapy so that no patient was classified
as undergoing a gross total resection. The predominant reason for the
proton therapy referral was locally invasive disease (15 patients had a
cavernous sinus invasion). Proton therapy was delivered as adjuvant
treatment in 11 patients, salvage therapy for a recurrence in 5
patients, and definitive treatment in 1 patient. For patients undergoing
adjuvant therapy, the median interval from surgery to initiation of
proton-based irradiation was 114 days (range, 45–283 days).

Radiation treatment

All 17 patients were treated with three-dimensional double-scattered
conformal proton therapy (3DCPT) in a continuous course of 5 fractions
per week at 1.8 Gy relative biological effectiveness (RBE) per fraction.
For each patient, pre- and postoperative treatment planning MRIs were
co-registered to the treatment planning CT. Target volumes were defined
as both the pre- and postoperative gross tumor volumes, with the
clinical target volume (CTV) adding a 5-mm margin off the gross tumor
volume to account for tumor spread. The planning target volume (PTV) was
defined as the CTV with an additional 3-mm margin. Two 3-field beam
arrangements were used—either a mohawk (Figure 1A) or a 2-
lateral oblique, superior-anterior oblique arrangement (Figure 1B).
Beam-shaping apertures were designed based on a customized expansion of
the PTV projection in the beam’s eye-view of approximately 5 to 7 mm.
Customized beam compensators were individually designed to maximize dose
conformality and reduce the effects of tissue heterogeneity on the dose
distribution. Total dose ranged from 45 to 50.4 Gy (RBE) (median, 45 Gy
[RBE]). Plans were normalized such that 99% of the CTV was covered by
the prescription, which nearly always meant that 95% of the PTV received
95% of the prescription.

Statistical methods

JMP software (SAS Institute, Cary, NC) was used to compute the
Kaplan-Meier product limit estimates for local control, progression-free
survival, and cause-specific survival.

Results

Local control

The 3-year radiographic local control rate for both secreting and
non-functional pituitary adenomas after treatment with proton therapy
was 100%, meaning all patients exhibited either stabilization or
regression in tumor size. Objective measures of biochemical control were
not available for the 4 patients with secreting tumors. Of these, 3
patients reported no signs, symptoms or biochemical evidence that they
remained hypersecretory. It was not evident at what time their baseline
hypersecretion normalized. The patient with a tumor secreting growth
hormones continues to visit her local endocrinologist and reports no
endocrine-related symptoms.

Survival

The 3-year overall survival rate was 100%. There was 1 intercurrent
death that occurred at 4.98 years after treatment due to cardiovascular
disease.

Complications

Several factors potentially lead to adverse neurological events,
including surgery, radiation therapy, tumor mass effect, and hormonal
secretion. The most commonly observed side effect was hypopituitarism,
evident in 11 patients following RT. Table 2 shows the presence of
pituitary dysfunction after both surgery and RT. All but 1 of the
patients who were hormone-deficient after proton therapy had baseline
pituitary dysfunction. In this series, no other major complications,
such as cerebrovascular accidents, decline in visual function,
ototoxicity, and second malignancies, have been observed as of the most
recent follow-up. Objective neurocognitive function was not available
for most patients, but all patients who were alive at the time of data
collection report no signs or symptoms of significant cognitive
deficits.

Dosimetric outcomes

Dosimetric data were reviewed for all 17 proton plans. In addition, 4
IMRT comparison plans were generated, normalized to the same target
coverage achieved with the proton plans. Table 3 shows the mean maximum
doses to serial organs at risk (OARs) for both the 3DCPT and IMRT plans.
Compared to the IMRT plans, the left and right retinae received lower
doses with 3DCPT; however, none of the doses delivered to serial OARs
with either technique are expected to result in significant normal
tissue complications. Nevertheless, these data show that proton therapy
did not result in any unacceptable physical dose heterogeneity within
serial OARs. Comparison of both maximum and mean doses to the whole
brain, temporal lobes, and hippocampi are presented in Table 4. On
average, the proton plans produced lower doses to whole brain, temporal
lobes and hippocampi. Average dose-volume histograms are shown in Figure
2, demonstrating that most of the benefits of proton therapy were seen
from a reduction in the low and moderate doses to these organ-at-risk
volumes (ORVs).

Discussion

In the management of pituitary adenomas, surgical resection alone
yields control rates that substantially differ by tumor characteristics.
A large series by Mortini and colleagues9 reported control
rates of 55.5% in macroadenoma patients, compared to 78.9% for
microadenomas. Much poorer outcomes were reported in tumors invading the
cavernous sinuses, at 7.4%. While surgical resection is often indicated
as a first line of treatment for these tumors, recurrence after surgery
alone is 19% vs. 2% in patients receiving surgery and RT.10
RT is an effective treatment modality either postoperatively when the
likelihood of recurrence is high, or definitively when tumors are
unresectable and cannot be medically managed.

Long-term outcomes of patients treated with postoperative
conventional RT have been well-documented in the scientific literature.
In one of the largest and most-cited analyses, Brada et al. reported the
outcomes of 411 patients, of which 252 had non-functioning adenomas,
131 had functional adenomas, and the remaining 28 were of unknown
secretory status. At 10 years, the progression-free survival rate was
94%, and at 20 years it was 88% for all patients. The only factor
affecting prognosis in this study was hormone secretion.11 In
2008, Chang et al. reported the outcomes of adjuvant RT in 663 patients
with nonfunctioning pituitary adenomas, with progression-free survival
rates of 93% at 5 years, 87% at 10 years, and 74% at 20 years. Out of
these patients, cavernous sinus involvement was the only significant
prognostic factor.12 Snead and colleagues reviewed the
records of 100 patients with pituitary adenomas, 69 of which were
nonfunctioning and 31 were functioning. Overall, the 10-year
progression-free survival rate was 95% for nonfunctioning and 88% for
functioning adenomas. No statistically significant variables influenced
prognosis in this study. 2 A 2009 study by Erridge et al.
reported the progression-free survival rate of 385 patients treated with
RT to be 97% at 10 years, and 96% at 20 years. No identifiable factors
affected control rates in this study.13

In contrast to conventional RT, the outcomes of patients treated with
fractionated proton therapy either definitively or adjuvantly are less
well-documented. While several studies have reported outcomes of both
conventional and proton-based SRS for treating pituitary adenomas, SRS
is best indicated for tumors < 3 cm in diameter and further than 5 mm
from the optic chiasm.4 In the only other series reporting
outcomes using fractionated proton therapy to date, Ronson and
colleagues analyzed 47 patients treated with fractionated proton
therapy. They observed 100% radiographic local control of all 41
patients who had available follow-up, with a median follow-up of 3.9
years.14 These control rates are consistent with our results
(100% at 3 years). A recent review by Loeffler et al. estimates that RT
achieves biochemical remission rates of approximately 50% at 10 years,
with these rates enhanced by concomitant medical management.4
Our series reports treatment of 4 patients with functioning tumors—2
with prolactinomas, 1 with a growth hormone-secreting tumor, and 1 with
an adrenocorticotropic hormone-secreting tumor. Unfortunately, objective
endocrine follow-up was unavailable in these patients. Nevertheless,
all 4 patients report no signs, symptoms or other evidence of
hypersecretion.

The most common complication of RT, by far, is hypopituitarism of 1
or more hormonal axes. The literature suggests that this toxicity
requires many years to develop. With fractionated RT,
radiation-associated endocrinopathies is seen in roughly 20% of patients
after 5 years of follow-up. Some studies have revealed pituitary
decline to reach as high as 80% in patients after 10 years of follow-up
data.4 In our series, only 5 patients had normal pituitary
function before RT, while the remainder had existing postoperative
pituitary dysfunction. We observed 1 of those 5 patients develop
new-onset hypopituitarism associated with RT (Table 2). With our median
follow-up of 3.9 years, this rate is consistent with the current
literature.

Other documented complications of RT include visual decline,
cerebrovascular accidents, ototoxicity, temporal lobe necrosis, and
secondary brain tumors. These toxicities are fortunately rare, and often
do not manifest until many years after treatment. Perhaps the most
documented of these extra-pituitary events is injury to the optic
pathways, with a 1.5% likelihood at 20 years after RT, and
radiation-induced tumors, likely in 1.9% at 20 years.11,13
Ronson and colleagues reported 1 case of temporal lobe necrosis 19
months after treatment. Several factors may have contributed to this
event, but it is noteworthy that this patient received 54 Gy (RBE) in 2
Gy fractions.14 While, fortunately, we report none of these
complications in our series, continued follow-up is required to
adequately assess such toxicities, as the incidence of these events
slowly rises over time.

The rationale for particle therapy treatment such as fractionated
proton therapy stems from a phenomenon known as the Bragg peak, which
allows dose escalation to a target volume while sparing adjacent
peripheral structures. Proton therapy has garnered particular interest
in the treatment of intracranial tumors, especially as the importance of
neuroprotection in radiation therapy is becoming increasingly realized.
Neural stem cells serve a central role in neuroplasticity, with
reserves located primarily in the subventricular zone as well as the
subgranular layer of the hippocampal dentate gyrus.15,16
Conventional radiation therapies that do not spare these areas have been
shown to damage hippocampal neurogenesis, contributing to the
neurocognitive decline in patients treated for many intracranial tumors.17,18
Dosimetric comparisons have established that proton-based modalities
have the potential to better spare these structures vs. conventional
techniques in treating intracranial tumors.8,9

Recent prospective data support these hypotheses; increased doses to
the temporal lobes and hippocampi significantly impair patients’
performances on standardized neurocognitive tests.20 Dose-cognitive
effect models have also been applied in dosimetric comparisons to
estimate the improved preservation of IQ in patients who receive proton
therapy.21 But the relationship between brain irradiation and
neurocognition is not entirely agreed upon. Some cross-sectional
studies have found no significant differences in cognitive performance
between patients with pituitary adenomas receiving surgery plus
postoperative conventional RT, and patients receiving surgery alone.22,23
These studies analyzed patients with median ages between 55 and 61,
whereas the Redmond et al. study included only pediatric patients.20
The patients in our study have a median age of 63 years, yet ages range
from 10-83; thus, our findings may be difficult to apply uniformly. In
addition, ongoing clinical trials such as RTOG 0933 aim to further
assess the potential benefits of hippocampal avoidance and the
relationship between radiation dose and cognitive function.

Our dosimetric analysis aimed to assess dosage differences in several
serial OARs by comparing the 17 proton treatment plans used in our
patients to 4 equivalent IMRT plans generated from our series. Of note,
temporal lobe and hippocampal avoidance were objectives in the IMRT
planning process. Despite specific goals to avoid these structures in
IMRT planning, the whole brain, both temporal lobes, and both hippocampi
were spared using 3DCPT. Dose-volume histograms of the 5 aforementioned
structures also show significant decreases in the volume receiving up
to 10 Gy (RBE; V10) in all 5 structures, as well as the V20 of the whole
brain. Reducing doses to structures outside the tumor volume may
potentially mitigate the unwanted effects of therapy on surrounding
tissues. While we used no objective measures of neurocognitive function
during follow-up of our patients, the dosimetric advantages
characterized in our series may be of further interest given our growing
understanding of RT doses to specific brain structures and cognitive
impairment.

Conclusion

Our study demonstrates the feasibility of delivering proton therapy
for pituitary adenoma. The high conformality of proton therapy does not
appear to compromise local control and there is no increased early
toxicity. Given the results of RTOG 0933, the lower dose to the
hippocampi and temporal lobes should reduce the neurocognitive impact of
radiotherapy. This greatest benefit will likely be in younger patients
who are expected to have long-term survival.

About the Author

Mr. Kennedy is a medical student at the University of Florida,
Gainesville; Dr. Dagan is an assistant professor, University of Florida
Health Proton Therapy Institute, Jacksonville, and University of Florida
Department of Radiation Oncology, Gainesville. Dr. Rotondo is an
assistant professor, University of Florida Health Proton Therapy
Institute, and University of Florida, Department of Radiation Oncology.
Ms. Louis is a medical dosimetrist at University of Florida Health
Proton Therapy Institute. Mr. Morris is a biostatistician, University of
Florida Health Proton Therapy Institute and University of Florida,
Department of Radiation Oncology. Dr. Indelicato is an associate
professor, University of Florida Health Proton Therapy Institute, and
University of Florida, Department of Radiation Oncology.